Continuing progressive deterioration of the environment in the Aral Sea Region: disastrous effects on mother and child health.

UNLABELLED: Scientists, non-governmental experts (NGOs) and governmental officials from the Central Asian Republics and an international group of invited scientists and NGO representatives participated in a workshop on the disastrous health problems in the Aral Sea Region. Various serious problems were reported in more than 20 presentations. Particular emphasis was put on the way in which adverse environmental factors such as contaminated water and food have contributed to the deterioration of human health, particularly that of mothers and children. CONCLUSION: There is an urgent request that the international community assists local scientists to develop programmes to improve the health of the population in the Aral Sea Region.

The ontogeny of the gut mucosal immune system and the susceptibility to infections in infants of developing countries.

In this review we summarize data on the human gut mucosa associated lymphatic tissues as part of the common mucosal immune system. Its embryonal-fetal and post-natal ontogeny becomes severely distorted and compromised by mal-/undernutrition which is so prevalent in developing countries. Pathogenetic interdependencies exist between maternal-fetal undernutrition, the ontogeny of the immune system, constant antigenic stimulation of the mucosal immune system post-natally, and the 14 million deaths annually from infections in children below the age of 5 years in developing countries. A detailed knowledge of these interdependencies is required for effective prevention and treatment in an attempt to reduce the high morbidity and mortality rates of children in developing countries.

Minimal residual disease in vitro of a pre-B-lymphoma.

We have studied the survival of clonogenic neoplastic cells of a murine pre-B-lymphoma (BCl-1) of the spleen in culture. We have found quantitative deficiencies such as reduced surface adherence of stromal cells and impaired CFU-F (colony forming units-fibroblast) and pre-CFU-F colony and layer formation in stromal cultures of lymphoma bearing spleen, as compared to cultures from normal spleen. There are two populations of clonogenic BCl-1 lymphoma cells surviving in culture: one population is surface adherent, and the other is non-adherent. Both populations transmit the lymphoma to healthy indicator mice. We hope that this model will be helpful in studying minimal residual leukemic disease [1] in culture.

Cancer morbidity rates of children from the vicinity of the nuclear power plant of Würgassen (FRG).

The morbidity rates from neoplastic disease have been studied in children below the age of 15 years, residing at the time of their diagnosis within a diameter of 25 km of the nuclear power plant of Würgassen (FRG). A total of 42 patients were registered between the years of 1980 and 1988: 15 patients with neoplasms of the hematolymphopoietic system, 14 neoplasms of the central nervous system (CNS), and 13 with solid tumors outside of the CNS. The data show that children living in the vicinity of this nuclear power plant do not have an increased risk of developing neoplastic disease, as compared to the entire pediatric population of the FRG. However, a tendency for an elevated risk, not reaching the level of statistical significance, cannot be fully excluded.

Paediatric oncology in developing countries.

Paediatric oncology in developing countries is a specialty in its own right that has so far been largely neglected by the western medical profession. It has specific features of genetic cancer predisposition and of external factors influencing phenotypic cancer manifestations. We point out here some of the specific features of cancer presentation in children of developing countries.

Improved prognosis in mice with advanced myeloid leukemia following administration of GM-CSF and cytosine arabinoside.

Acute myeloid leukemia (AML) was induced in C57Bl mice through the i.v. innoculation of C-1498 cell line. One week later, i.e. at mid-term disease, the leukemic mice received an i.p. injection of 200 ng rmGM-CSF and 24 h later, two consecutive i.p. cytosine arabinoside (ara-C) injections at 6 h intervals (2 x 200 mg/kg). The leukemic mice received 3-4 weekly courses of combined therapy and survived 4-5 weeks following leukemia induction. Control mice received ara-C only and survived 2-3 weeks. Moreover, leukemic mice administered both GM-CSF and ara-C had a lower marrow leukemic load than mice treated with ara-C only. From these findings, we conclude that therapy of murine AML with combined rmGM-CSF and ara-C is more effective than ara-C only. Leukemic mice treated with GM-CSF and ara-C had a longer life expectancy and a smaller leukemic load than mice administered ara-C only.

Bone marrow stromal elements in murine leukemia: decreased CSF-producing fibroblasts and normal IL-1 expression by macrophages.

A study of bone marrow stromal elements in murine acute myeloid leukemia (AML) was carried out. Our previous studies had indicated marrow stromal deficiency in murine AML. In the current investigation, separate stromal cells were cultured and the results obtained have shown that, while marrow stromal macrophages are normal in leukemia and express adequate amounts of IL-1, the fibroblasts are markedly reduced. However, if sufficient fibroblasts are pooled in vitro, they produce adequate amounts of CSF. Test of TNF alpha in leukemic cells CM, as possible cause of marrow stromal inhibition in leukemia, had not disclosed this cytokine. Further, it was observed that total body lethal irradiation of leukemic mice aggravates the stromal deficiency, confirming results of our previous investigations. It is concluded that bone marrow stromal deficiency in murine AML is due to decreased fibroblasts and, implicitly, reduced CSF production.

Cumulative bone marrow stromal damage caused by X-irradiation and cytosine-arabinoside in leukemic mice.

A study of treated murine acute myeloid leukemia (AML) with an emphasis on the bone marrow stromal function is reported. Leukemia was induced in C57Bl mice through intraperitoneal (i.p.) inoculation of C-1498 myelogenous leukemic cells. The leukemic mice were administered: (1) total body lethal X-irradiation (t.b.i.); (2) two i.p. cytosine-arabinoside (Ara-C) injections followed by X-irradiation. Control mice received similar regimens. Bone marrow of experimental and control mice was processed for stromal cell cultures (SCC) and in vitro engraftment of hematopoietic cells onto the cultures. The results of this study indicate that the bone marrow stromal deficiency which occurs in leukemia is aggravated by Ara-C and irradiation treatments. Moreover, SCC of treated leukemic mice sustain in vitro hematopoiesis only to a limited degree. Stromal deficiency, as possible cause for graft failure in bone marrow transplanted leukemic patients, is discussed.

Long-term survival of murine erythroid progenitors in long-term bone marrow culture and stromal cell culture: differentiation in peritoneal diffusion chamber culture.

Bone marrow cells of normal and cytosine-arabinoside (Ara-C) treated C57B1 mice were cultured in primary long-term culture (LTBMC) for a period of eight weeks. Non-adherent cells collected at weekly culture feedings consisted of neutrophils, macrophages and megakaryocytes. These were transferred into a) secondary peritoneal diffusion chamber cultures (DC) and b) secondary stromal cell cultures (SCC) first, and then into tertiary DC cultures. While in LTBMC and SCC there was no evidence of erythropoiesis, many erythroid colonies developed in DC cultures. It appears that undifferentiated erythroid progenitors may have a long survival in LTBMC and SCC devoid of erythropoietin and then differentiate in vivo in DC cultures in host mice without specific erythropoietic stimuli. Terminal differentiation and maturation of erythroid progenitors occurs to a limited extent in conventional DC cultures. The large number of erythroid colonies in DC observed in the present study could be due to increased sensitivity of undifferentiated erythroid progenitors from LTBMC to physiological levels of Epo in host mice of DC.

Enhanced capacity of cytosine-arabinoside-treated murine bone marrow to maintain hematopoiesis in long-term culture.

A study of bone marrow of C57B1 mice administered cytosine-arabinoside (Ara-C) was carried out in long-term bone marrow culture (LTBMC). Two days after administration of two consecutive i.p. Ara-C injections (200 mg/kg each) at 6-h intervals, the bone marrow becomes hypocellular, yet in the process of regeneration, with an enriched and/or concentrated content of progenitors and stem cells. Ara-C-treated marrow was observed to sustain hematopoiesis in vitro better than physiological marrow; it produced a higher cell yield, a higher proportion of young-type myeloid cells, and higher levels of granulocyte-macrophage colony-forming cells and colony-forming units in diffusion chamber than control marrow. In addition, stromal cell cultures (SCC), devoid of hematopoiesis and engrafted with hematopoietic cells from LTBMC of Ara-C-treated marrow, were observed to produce hematopoietic cells for longer periods of time than SCC engrafted with control cells. In view of its increased capacity for regeneration, it is suggested that regenerative marrow should be used in autologous bone marrow transplantation in humans.

The effect of L-asparaginase on lipid metabolism during induction chemotherapy of childhood lymphoblastic leukaemia.

L-asparaginase is an effective antileukaemic drug and a potent inhibitor of hepatic protein synthesis. Its effect on lipid metabolism was studied in two cohorts of children with ALL, one of whom received L-asparaginase concomitantly with three other drugs (protocol BFM 79). In the second protocol (BFM 83) administration of L-asparaginase was arranged to follow the other three drugs in time sequence. The two major findings of this study were elevated serum levels of total cholesterol and a strong increase in serum triglycerides. The former change was due to an increase in alpha-cholesterol and could not be attributed to L-asparaginase because it was also found following protocol BFM 83 before the administration of the drug. Elevations of total triglycerides were due to high levels of exogenous chylomicron bound triglycerides and were limited in occurrence almost exclusively to the period of L-asparaginase monotherapy. Hypothyroidism was excluded as a possible pathogenetic mechanism. These changes in lipid metabolism induced by L-asparaginase during intensive remission induction chemotherapy are fully reversible.

Pre CFU-F in bone marrow cultures from children with hematopoietic disease including acute leukemia.

Stromal precursor cells from bone marrow aspirates of children have been studied in culture. In 7 day liquid cultures normal individuals and patients with acute leukemia in remission grew 110 +/- 50 CFU-F and 100 +/- 40 CFU-F (colony forming unit--fibroblasts) respectively, per 6 X 10(5) buffy coat mononuclear cells. Staining with monoclonal antibodies suggests that stromal cells from CFU-F colonies are fibroblasts. CFU-F colony growth from the bone marrow of patients with active leukemia was low. After cultivation periods of more than 21 days, we observed, in addition, still more immature, clonogenic fibroblast precursor cells, "pre CFU-F", and round cells attached to stromal cells from pre CFU-F colonies. From the round cells, we have passaged pre CFU-F and CFU-GM (colony forming unit--granulocytic, monocytic) in secondary cultures. Our observations are in agreement with the concept that the bone marrow stromal cell matrix serves as a sanctuary for reversibly attached clonogenic cells of both the hematopoietic and fibroblast lineages.

CFU-F circulating in cord blood.

CFU-F (colony forming units-fibroblast) were studied from cord blood and, as controls, from normal bone marrow of older children and adults. Numbers of CFU-F in cord blood buffy coat cells are lower by a factor of 10 in comparison to bone marrow CFU-F. Cytomorphology and staining with monoclonal antibody identify the progeny cells of CFU-F as fibroblasts. Cord blood CFU-F derived fibroblasts have properties supporting hematopoiesis: They produce CSF (colony stimulating factor) to which fresh cord blood CFU-GM (colony forming units-granulocytic, monocytic) react by colony formation in a dose-response manner. In addition, fibroblast colonies discharge clonogenic round cells into the medium forming CFU-GM and CFU-F colonies in secondary methyl cellulose cultures. We conclude that fetal blood contains clonogenic stromal cells (CFU-F) that give rise to fibroblasts with properties of hematopoietic support.

[High dosage ARA-C in combination with mitoxantrone in therapy of acute myeloid leukemia in childhood. Initial results of the AML BFM-85 recurrence study]. / Hochdosiertes ARA-C in Kombination mit Mitoxantron bei der Therapie der AML im Kindesalter. Erste Ergebnisse der AML-Rezidivstudie BFM-85.

19 children with AML were treated using the combination of high dose cytosine-arabinoside and mitoxantrone. All children were initially treated according to protocol AML-BFM-83. 6 children with refractory AML, 9 children with bone-marrow relapse during or after maintenance therapy and 4 children with residual blasts (5-25%) after remission induction and consolidation therapy AML-BFM 83 were treated with the relapse protocol. 6 of 15 children with refractory AML and all 4 children with residual blasts achieved a complete remission. 2 children died in bone-marrow aplasia and 1 child did not respond. One child died after further mitoxantrone treatment due to toxic cardiomyopathy. All children went into severe bone marrow aplasia, which lasted in median 27 days. These data indicate a high antileukemic activity of HD-ARA C/mitoxantrone in childhood AML.

Clinical symptoms and biochemical properties of three new glucosephosphate isomerase variants.

Glucosephosphate isomerase deficiency as the cause of macrocytic congenital nonspherocytic hemolytic anemia is described in three unrelated families. The biochemical properties of the variant glucosephosphate isomerases indicate that the patients have new variants, designated as GPI Kiel, GPI Hamburg, and GPI Homburg. The severity of the clinical symptoms depended on the amount of residual GPI activity and the biochemical properties of the variant enzyme. Thus the patient with GPI Kiel (34% residual activity) whose variant GPI was slightly unstable showed a mild chronic hemolytic anemia. The patient with GPI Homburg (7% residual activity) whose variant enzyme was stable and had a reduced specific activity, suffered from severe congenital hemolytic anemia and neuromuscular symptoms. Due to the special properties of GPI Homburg, we assume that both the hematological and neuromuscular symptoms of the patient with GPI Homburg are caused by his GPI deficiency. The twins with GPI Hamburg (27% residual activity) had a distinctly unstable variant enzyme and had suffered from hemolytic crises since birth. Only GPI Homburg showed an altered electrophoretic mobility and an increased affinity for fructose-6-phosphate. The other two variants had normal values.